L0301P45 - Introduction to Pharmacodynamics
Drug Receptor Interactions *binding between the drug and receptor *normally activates some sort of transduction (second messenger) system *T = transducer *D = drug *R = receptor Occupation Theory Models *formation of drug-receptor complex leads to “stimulus” *producing a biological response *response is proportional to the amount of  drug-receptor complexes formed *i.e. the more receptor sites are occupied by drug molecules, the greater the response Concentration-Response Curves *drawn on a log scale to cater for more data on the x-axis and clearer spread on y-axis Clark’s Model *used in the past *magnitude of the response is proportional to the formation of DR complexes - E∝DR *maximal response occurs when all receptors are occupied i.e. Emax∝Rt **where Rt = total [ ] of receptor sites *Rfree = Rt - DR Stephenson’s Model *modifications to Clark's model *introduced the concept of efficacy *proposed that a full agonist could produce a maximal response when occupying fewer than 100% of receptors *provided evidence that some tissues produce a max response when only a very small fraction of the receptors are occupied *example: neuromuscular junction **has 30million ACh receptor **activation of on 40,000 is required for action potential to be transmitted **thus there is a receptor reserve in tissues Spare Receptors *the percentage of available receptors leftover after a maximal response is produced by a full agonist *leftover percentage = receptor reserve Partial Agonist *have affinity (similar to agonist) *have efficacy, but lower than a full agonist *the receptor-effector coupling efficiency is lower than that of full agonist *produce less stimulus when occupying the same number of receptors as a full agonist *have potential to act as antagonists - prevents other drugs from binding *in diagram L,N = full  M = partial agonist EC50 (Effective Concentration 50) *agonist concentration that produces a response which is 50% of maximum *measure of agonist potency Drug Concentration Response Graph *no partial agonists - all full agonists *highest potency - A - to the left **less drug for same response *EC50 of drug C - 10nM/L *greatest efficacy (%response) - all the same Definitions *'potency' - relates to the concentration of a drug at which it produces its effect *'affinity' - ability to bind at a receptor site *'efficacy' - ability of a substance which has bound at a receptor site to generate “stimulus” hence to produce a biological effect, a measure of receptor-effector coupling efficiency Antagonism Types *chemical (combine in solution) *physiological *pharmacokinetic *pharmacodynamic Antagonists *may bind at the receptor site **i.e. have affinity **e.g. competitive antagonists *binding to the site do not produce a biological effect **i.e. they have no efficacy *can be of various types **i.e. competitive reversible, non-competitive, competitive irreversible Competitive Antagonism *occupies the site but generates no stimulus *agonist is unable to bind *no stimulus = no ion flux = no response Reversible *can always be overcome with higher concentration of agonists (more agonist = higher chance of binding with a receptor) *surmountable (no depression of max response) Irreversible *drug binds covalently at receptor site and do not detach from the receptor *agonist is unable to bind *no stimulus = no ion flux= no response *example: phenoxybenzamine **not used as a drug due to its irreversibility Non-Competitive Antagonism *drug binds to a different site on the receptor *binding of the antagonist causes conformational change meaning that usual substrate/agonist cannot bind Antagonist Potency (pA2) *the pA2 is the negative log10 of the antagonist concentration in the presence of which it is necessary to double the agonist concentration to produce the same response as was obtained in the absence of antagonist *the pA2 determination is only relevant when the antagonism is competitive *the antagonist concentration required to move graph two times to the right **lower [ ] = higher antagonist potency Uses *to compare the relative potency of two *competitive antagonists *receptor classification: **different agonists acting on the same tissue **same antagonists acting on different tissues Inverse Agonists *past: did not understand how “antagonists” sometimes produced a side effect *turning off the receptor which was previously activated (in a state of excitation) *reduce the level of activation of a receptor *particularly important at constitutively active G-protein receptors (i.e. agonist independent) *e.g. antihistamines